Browsing UMB Coronavirus Publications by Author "Rosales, Romel"
Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanismsGordon, David E; Hiatt, Joseph; Bouhaddou, Mehdi; Rezelj, Veronica V; Ulferts, Svenja; Braberg, Hannes; Jureka, Alexander S; Obernier, Kirsten; Guo, Jeffrey Z; Batra, Jyoti; et al. (American Association for the Advancement of Science, 2020-12-04)The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.
Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19Boras, Britton; Jones, Rhys M; Anson, Brandon J; Arenson, Dan; Aschenbrenner, Lisa; Bakowski, Malina A; Beutler, Nathan; Binder, Joseph; Chen, Emily; Eng, Heather; et al. (Springer Nature, 2021-10-18)COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.